Biochemistry, Computational Biology
University of Washington
Dr. Baker is also a professor of biochemistry and an adjunct professor of genome sciences, bioengineering, chemical engineering, computer science, and physics at the University of Washington, Seattle.
Design of New Functional Proteins
By analyzing the architecture and forces that create naturally occurring proteins, David Baker draws inspiration for a new breed of synthetic functional proteins. These designer molecules hold the potential to fulfill a range of functions that evolution has yet to tackle, such as nanowires and molecular cages, catalysts for nonbiological reactions, and new protein-based drugs.
Nearly two decades ago, Baker and his team created a computer algorithm called Rosetta. The program predicts the structures of naturally occurring proteins by searching for their lowest energy states: proteins generally assume conformations that have the lowest energy, and as a consequence, the greatest stability.
Since then, Baker has harnessed Rosetta’s power to create new protein structures and functions. For example, HB36 is a synthetic protein that targets a region of the flu virus shared by multiple strains. When tested in animals, HB36 protected the animals against the virus.
In the past several years, Baker’s team has demonstrated the potential for a new generation of functional proteins with sequences and structures not found in nature. Such synthetic proteins could help address current health challenges by advancing protein-based therapeutics, informing the next generation of medicine, or even helping break down toxic molecules in the environment.
Baker is also an advocate of involving the public in scientific research. To that end, he and his collaborators developed a citizen-science offshoot of Rosetta called Rosetta@home, which sends his team’s prediction and design calculations to volunteers’ computers during idle hours and collects the results for analysis. The researchers also created Foldit, an interactive protein-folding game that allows Baker to enlist human intuition in his prediction and design efforts.
A protein’s folded, three-dimensional shape is dictated by how its atoms either attract or repel each other and the water molecules that surround them. Even in a small protein, trillions of potential interactions create an unlimited number of possible shapes. But evolution has only tapped into a very small percentage of these protein-folding patterns. To design a wide range of new proteins from scratch, David Baker and his group are investigating the rules that govern protein folding.
Baker’s interest in protein folding began when he was a senior at Harvard University. “We had to write a term paper on something to do with biochemistry, and I asked the professors if I could look at protein folding. They discouraged me, saying ‘no one really knows how it works.’” Baker left the question alone, but it continued to nag at him. He finally revisited the topic after starting his own research lab at the University of Washington.
To tackle the protein structure prediction problem, in 1998, Baker and coworkers created a program called Rosetta. The program, now used by researchers globally, can predict the structures of small proteins from their amino acid sequences. But because the calculations needed to predict proteins are extremely time intensive, Baker developed a version of Rosetta in 2004 that anyone could load on their home computer to help perform some of the algorithm’s calculations. By early 2008, nearly 200,000 volunteers had downloaded and installed Rosetta@home. And, after some of the volunteers expressed their desire to help guide the folding of proteins on their computer screens, Baker developed and released “Foldit,” a multiplayer online protein-folding game.
“The dream is that people working together all around the world can make a significant contribution to science and global health,” says Baker. Rosetta@home volunteers and Foldit players continue to make a number of invaluable contributions to Baker’s research projects.
More recently, Baker’s focus has shifted from computing the structures of naturally occurring proteins to designing and building proteins from scratch. “It’s not such a leap to start thinking about making new amino acid sequences that encode new structures,” he explains.
The process, called de novo protein design, allows Baker and his team to create brand-new proteins with sequences that are unlike anything seen in nature. So far, they have designed proteins that protect animals against the flu, catalyze chemical reactions, sense small molecules, and assemble into new materials. He reasons that while naturally occurring proteins elegantly solve the problems that arose during evolution, modern-day challenges require new proteins with new functions. His goal: to develop a whole new world of synthetic proteins to address such issues in medicine, energy, and technology.
“My philosophy is, if you’re going to tackle a problem, you should really go all out,” he says. “Most interesting problems aren’t going to be solved if you go at them halfheartedly.”